Anticancer effects of brusatol in nasopharyngeal carcinoma through suppression of the Akt/mTOR signaling pathway
Anticancer effects of brusatol in nasopharyngeal carcinoma through suppression of the Akt/mTOR signaling pathway
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DOI：
10.1007/s00280-020-04083-3
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发表时间：
2020-05-24
影响因子：
3
通讯作者：
Zhang, Zhenfeng
中科院分区：
文献类型：
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作者：
Guo, Songbin;Zhang, Jinling;Zhang, Zhenfeng
目的 鸦胆子醇是从传统中草药鸦胆子中分离出来的天然苦木素，对多种人类癌症具有生物活性，但其对鼻咽癌（NPC）的作用尚未见报道。本研究旨在探讨布鲁萨醇在体内外对鼻咽癌的作用及其分子机制。方法通过MTT和集落形成试验评估布鲁萨醇的抗增殖作用。通过流式细胞术测定细胞凋亡。通过蛋白质印迹分析测定线粒体凋亡、细胞周期停滞和 Akt/mTOR 途径蛋白的表达。在裸鼠模型中进行了进一步的体内验证。结果 Brusatol 对四种人鼻咽癌细胞系（CNE-1、CNE-2、5-8F 和 6-10B）具有剂量依赖性的抗增殖活性。这种抗增殖作用伴随着线粒体凋亡和细胞周期停滞，这是通过调节几个关键分子靶标（例如 Bcl-xl、Bcl-2、Bad、Bax、PARP、Caspase-9、Caspase-7、Caspase-3、Cdc25c、Cyclin B1、Cdc2 p34 和 Cyclin D1）来实现的。此外，我们发现 brusatol 抑制 Akt、mTOR、4EBP1 和 S6K 的激活，表明 Akt/mTOR 通路是 brusatol 抑制生长和促进细胞凋亡的关键潜在机制。进一步的体内裸鼠模型证明，布鲁萨醇显着抑制CNE-1异种移植物的生长，且无明显毒性。结论 这些观察结果表明，brusatol 是一种有前途的抗肿瘤候选药物，或者是当前治疗鼻咽癌化疗药物的补充。
Purpose Brusatol, a natural quassinoid that is isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, possesses biological activity in various types of human cancers, but its effects in nasopharyngeal carcinoma (NPC) have not been reported. This study aimed to explore the effect and molecular mechanism of brusatol in NPC in vivo and in vitro. Methods The antiproliferative effect of brusatol was assessed by MTT and colony formation assays. Apoptosis was determined by flow cytometry. The expression of mitochondrial apoptosis, cell cycle arrest, and Akt/mTOR pathway proteins were determined by western blot analysis. Further in vivo confirmation was performed in a nude mouse model. Results Brusatol showed antiproliferative activity against four human NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) in a dose-dependent manner. This antiproliferative effect was accompanied by mitochondrial apoptosis and cell cycle arrest through the modulation of several key molecular targets, such as Bcl-xl, Bcl-2, Bad, Bax, PARP, Caspase-9, Caspase-7, Caspase-3, Cdc25c, Cyclin B1, Cdc2 p34, and Cyclin D1. In addition, we found that brusatol inhibited the activation of Akt, mTOR, 4EBP1, and S6K, suggesting that the Akt/mTOR pathway is a key underlying mechanism by which brusatol inhibits growth and promotes apoptosis. Further in vivo nude mouse models proved that brusatol significantly inhibited the growth of CNE-1 xenografts with no significant toxicity. Conclusions These observations indicate that brusatol is a promising antitumor drug candidate or a supplement to current chemotherapeutic therapies to treat NPC.